No

Beta Blocker, Nonselective; Ophthalmic Agent, Antiglaucoma

Ophthalmic dosage form used to treat elevated intraocular pressure such as glaucoma or ocular hypertension; oral dosage form used for treatment of hypertension and angina, to reduce mortality following myocardial infarction, and for prophylaxis of migraine

C (per manufacturer); D (if used in 2nd and 3rd trimesters, based on expert analysis)

Hypersensitivity to timolol or any component; sinus bradycardia; sinus node dysfunction; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; uncompensated cardiac failure; bronchospastic disease; pregnancy (2nd and 3rd trimesters)

Administer cautiously in compensated heart failure and monitor for a worsening of the condition. Avoid abrupt discontinuation in patients with a history of CAD; slowly wean while monitoring for signs and symptoms of ischemia. Use caution with concurrent use of beta-blockers and either verapamil or diltiazem; bradycardia or heart block can occur. Beta-blockers can aggravate symptoms in patients with PVD. Patients with bronchospastic disease should generally not receive beta-blockers - monitor closely if used in patients with potential risk of bronchospasm. Use cautiously in diabetics because it can mask prominent hypoglycemic symptoms. Can mask signs of thyrotoxicosis. Can cause fetal harm when administered in pregnancy. Use cautiously in severe renal impairment: marked hypotension can occur in patients maintained on hemodialysis. Use care with anesthetic agents which decrease myocardial function. Can worsen myasthenia gravis. Similar reactions found with systemic administration may occur with topical administration.

Ophthalmic:

>10%: Ocular: Conjunctival hyperemia

1% to 10%: Ocular: Anisocoria, corneal punctate keratitis, keratitis, corneal staining, decreased corneal sensitivity, eye pain, vision disturbances

<1%: Systemic allergic reaction (angioedema, urticaria, rash)

Systemic:

>10%:

Central nervous system: Drowsiness, insomnia

Endocrine & metabolic: Decreased sexual ability

1% to 10%:

Cardiovascular: Bradycardia, palpitations, edema, congestive heart failure, reduced peripheral circulation

Central nervous system: Mental depression

Gastrointestinal: Diarrhea or constipation, nausea, vomiting, stomach discomfort

Respiratory: Bronchospasm

Miscellaneous: Cold extremities

<1% (Limited to important or life-threatening symptoms): Chest pain, arrhythmias, orthostatic hypotension, nervousness, headache, depression, hallucinations, confusion (especially in the elderly), thrombocytopenia, leukopenia, shortness of breath, nightmares, memory loss, Raynaud's phenomenon, rash, psoriasis, angioedema, urticaria

Symptoms of intoxication include cardiac disturbances, CNS toxicity, bronchospasm, hypoglycemia and hyperkalemia. The most common cardiac symptoms include hypotension and bradycardia; atrioventricular block, intraventricular conduction disturbances, cardiogenic shock, and asystole may occur with severe overdose, especially with membrane-depressant drugs (eg, propranolol); CNS effects include convulsions, coma, and respiratory arrest is commonly seen with propranolol and other membrane-depressant and lipid-soluble drugs.

Treatment includes symptomatic treatment of seizures, hypotension, hyperkalemia and hypoglycemia; bradycardia and hypotension resistant to atropine, isoproterenol or pacing may respond to glucagon; wide QRS defects caused by the membrane-depressant poisoning may respond to hypertonic sodium bicarbonate; repeat-dose charcoal, hemoperfusion, or hemodialysis may be helpful in removal of only those beta-blockers with a small V_d, long half-life or low intrinsic clearance (acebutolol, atenolol, nadolol, sotalol).

CYP2D6 enzyme substrate

Alpha-blockers (prazosin, terazosin): Concurrent use of beta-blockers may increase risk of orthostasis.

Clonidine: Hypertensive crisis after or during withdrawal of either agent (not reported with timolol ophthalmic solution)

Drugs which slow AV conduction (digoxin): Effects may be additive with beta-blockers.

Epinephrine (including local anesthetics with epinephrine): Timolol may cause hypertension.

Glucagon: Timolol may blunt hyperglycemic action.

Insulin and oral hypoglycemics: May mask symptoms of hypoglycemia.

NSAIDs (ibuprofen, indomethacin, naproxen, piroxicam) may reduce the antihypertensive effects of beta-blockers.

Salicylates may reduce the antihypertensive effects of beta-blockers.

Sulfonylureas: Beta-blockers may alter response to hypoglycemic agents.

Verapamil or diltiazem may have synergistic or additive pharmacological effects when taken concurrently with beta-blockers.

Blocks both beta₁- and beta₂-adrenergic receptors, reduces intraocular pressure by reducing aqueous humor production or possibly outflow; reduces blood pressure by blocking adrenergic receptors and decreasing sympathetic outflow, produces a negative chronotropic and inotropic activity through an unknown mechanism

Onset of hypotensive effect: Oral: Within 15-45 minutes

Peak effect: Within 0.5-2.5 hours

Duration of action: ~4 hours; intraocular effects persist for 24 hours after ophthalmic instillation

Protein binding: 60%

Metabolism: Extensive first-pass effect; extensively metabolized in the liver

Half-life: 2-2.7 hours; prolonged with reduced renal function

Elimination: Urinary excretion (15% to 20% as unchanged drug)

Children and Adults: Ophthalmic: Initial: 0.25% solution, instill 1 drop twice daily; increase to 0.5% solution if response not adequate; decrease to 1 drop/day if controlled; do not exceed 1 drop twice daily of 0.5% solution

Adults: Oral:

Hypertension: Initial: 10 mg twice daily, increase gradually every 7 days, usual dosage: 20-40 mg/day in 2 divided doses; maximum: 60 mg/day

Prevention of myocardial infarction: 10 mg twice daily initiated within 1-4 weeks after infarction

Migraine headache: Initial: 10 mg twice daily, increase to maximum of 30 mg/day

Oral product should be administered with food at the same time each day

Administer other topically applied ophthalmic medications at least 10 minutes before Timoptic-XE®; wash hands before use; invert closed bottle and shake once before use; remove cap carefully so that tip does not touch anything; hold bottle between thumb and index finger; use index finger of other hand to pull down the lower eyelid to form a pocket for the eye drop and tilt head back; place the dispenser tip close to the eye and gently squeeze the bottle to administer 1 drop; remove pressure after a single drop has been released; do not allow the dispenser tip to touch the eye; replace cap and store bottle in an upright position in a clean area; do not enlarge hole of dispenser; do not wash tip with water, soap, or any other cleaner

Blood pressure, apical and radial pulses, fluid I & O, daily weight, respirations, mental status, and circulation in extremities before and during therapy

It is important to recognize that timolol eye drops may have systemic effects, particularly when patients are also on oral beta-blocker therapy or therapy with other negative chronotropic agents.

Myocardial infarction: Beta-blockers, in general without intrinsic sympathomimetic activity (ISA), have been shown to decrease morbidity and mortality when initiated in the acute treatment of myocardial infarction and continued long-term. In this setting, therapy should be avoided in patients with hypotension, cardiogenic shock, or heart block.

Surgery: Atenolol has also been shown to improve cardiovascular outcomes when used in the perioperative period in patients with underlying cardiovascular disease who are undergoing noncardiac surgery. Bisoprolol in high-risk patients undergoing vascular surgery reduced the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction.

Atrial fibrillation: Beta-blocker therapy provides effective rate control in patients with atrial fibrillation.

Angina: Beta-blockers are effective in the treatment of angina as monotherapy or when combined with nitrates and/or calcium channel blockers. In patients with severe intractable angina requiring negative cardiac chronotropic medications, pacemaker placement has been carried out to maintain heart rate in the setting of large doses of beta-blockers and/or calcium channel blockers. Beta-blockers are ineffective in the treatment of pure vasospastic (Prinzmetal) angina.

Withdrawal: Beta-blocker therapy should not be withdrawn abruptly, but gradually tapered to avoid acute tachycardia and hypertension.

Heart failure: There is emerging evidence that beta-blocker therapy, without intrinsic sympathomimetic activity (ISA), should be initiated in select patients with stable congestive heart failure (NYHA Class II-III). To date, carvedilol, sustained release metoprolol, and bisoprolol have demonstrated a beneficial effect on morbidity and mortality. It is important that beta-blocker therapy be instituted initially at very low doses with gradual and very careful titration.

May cause dizziness or fatigue; may rarely cause anxiety, depression, or hallucinations

Barbiturates and carbamazepine may decrease the effects of beta-blockers

No information available to require special precautions

No effects or complications reported

Oral: Take exact dose prescribed; do not increase, decrease, or discontinue dosage without consulting prescriber. Take at the same time each day. Does not replace recommended diet or exercise program. If diabetic, monitor serum glucose closely. May cause postural hypotension (use caution when rising from sitting or lying position or climbing stairs); dizziness, drowsiness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); decreased sexual ability (reversible); or nausea or vomiting (small frequent meals or frequent mouth care may help). Report swelling of extremities, respiratory difficulty, or new cough; weight gain (>3 lb/week); unresolved diarrhea or vomiting; or cold blue extremities. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Consult prescriber if breast-feeding.

Ophthalmic: For ophthalmic use only. Apply prescribed amount as often as directed. Wash hands before using and do not touch tip of applicator to eye or contaminate tip of applicator. Tilt head back and look upward. Gently pull down lower lid and put drop(s) inside lower eyelid at inner corner. Close eye and roll eyeball in all directions. Do not blink for 1/2 minute. Apply gentle pressure to inner corner of eye for 30 seconds. Wipe away excess from skin around eye. Do not use any other eye preparation for at least 10 minutes. Do not share medication with anyone else. Temporary stinging or blurred vision may occur. Immediately report any adverse cardiac or CNS effects (usually signifies overdose). Report persistent eye pain, redness, burning, watering, dryness, double vision, puffiness around eye, vision disturbances, other adverse eye response, worsening of condition or lack of improvement. Inform prescriber if you are or intend to be pregnant. Consult prescriber if breast-feeding.

Monitor for systemic effect of beta-blockade even when administering ophthalmic product

Gel, as maleate, ophthalmic (Timoptic-XE®): 0.25% (2.5 mL, 5 mL); 0.5% (2.5 mL, 5 mL)

Solution, as hemihydrate, ophthalmic (Betimol®): 0.25% (2.5 mL, 5 mL, 10 mL, 15 mL); 0.5% (2.5 mL, 5 mL, 10 mL, 15 mL)

Solution, as maleate, ophthalmic (Timoptic®): 0.25% (2.5 mL, 5 mL, 10 mL, 15 mL); 0.5% (2.5 mL, 5 mL, 10 mL, 15 mL)

Solution, as maleate, ophthalmic, preservative free, single use (Timoptic® OcuDose®): 0.25%, 0.5%

Tablet, as maleate, (Blocadren®): 5 mg, 10 mg, 20 mg

Botet C, Grau J, Benito P, et al, "Timolol Ophthalmic Solution and Respiratory Arrest," Ann Intern Med, 1986, 105(2):306-7.

Britman NA, "Cardiac Effects of Topical Timolol," N Engl J Med, 1979, 300(10):566.

Fraunfelder FT, "Ocular Beta-Blockers and Systemic Effects," Arch Intern Med, 1986, 146(6):1073-4.

Hoskins HD, Hetherington J Jr, Magee SD, et al, "Clinical Experience With Timolol in Childhood Glaucoma," Arch Ophthalmol, 1985, 103(8):1163-5.

Kligman EW and Higbee MD, "Drug Therapy for Hypertension in the Elderly," J Fam Pract, 1989, 28(1):81-7.

Levison SP, "Treating Hypertension in the Elderly," Clin Geriatr Med, 1988, 4(1):1-12.

Passo MS, Palmer EA, and Van Buskirk EM, "Plasma Timolol in Glaucoma Patients," Ophthalmology, 1984, 91(11):1361-3.

Vestal RE, Wood AJ, and Shand DG, "Reduced Beta-Adrenoceptor Sensitivity in the Elderly," Clin Pharmacol Ther, 1979, 26(2):181-6.

Wilkinson J, "Beta-Blocker Overdoses," Ann Emerg Med, 1986, 15(8):982.

Yin FC, Raizes GS, Guarnieri T, et al, "Age-Associated Decrease in Ventricular Response to Haemodynamic Stress During Beta-Adrenergic Blockade," Br Heart J, 1978, 40(12):1349-55.